RETRACTED: Functional and Topological Analysis of Pen-2, the Fourth Subunit of the γ-Secretase Complex (Withdrawn Publication. See vol. 299, 2023) (Retracted Article)

被引:38
作者
Bammens, Leen [1 ,2 ]
Chavez-Gutierrez, Lucia [1 ,2 ]
Tolia, Alexandra [1 ,2 ]
Zwijsen, An [2 ,3 ]
De Strooper, Bart [1 ,2 ]
机构
[1] Katholieke Univ Leuven, Ctr Human Genet, Lab Res Neurodegenerat Dis, B-3000 Louvain, Belgium
[2] Katholieke Univ Leuven VIB, Dept Mol & Dev Genet, B-3000 Louvain, Belgium
[3] Katholieke Univ Leuven VIB, Ctr Human Genet, Lab Dev Signaling, B-3000 Louvain, Belgium
关键词
AMYLOID PRECURSOR PROTEIN; CATALYTIC PORE; PRESENILIN ENDOPROTEOLYSIS; TRANSMEMBRANE DOMAIN-4; TERMINAL FRAGMENT; NOTCH; NICASTRIN; CLEAVAGE; APH-1; EXPRESSION;
D O I
10.1074/jbc.M110.216978
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The gamma-secretase complex is a member of the family of intramembrane cleaving proteases, involved in the generation of the A beta peptides in Alzheimer disease. One of the four subunits of the complex, presenilin, harbors the catalytic site, although the role of the other three subunits is less well understood. Here, we studied the role of the smallest subunit, Pen-2, in vivo and in vitro. We found a profound Notch-deficiency phenotype in Pen-2(-/-) embryos confirming the essential role of Pen-2 in the gamma-secretase complex. We used Pen-2(-/-) fibroblasts to investigate the structure-function relation of Pen-2 by the scanning cysteine accessibility method. We showed that glycine 22 and proline 27 in hydrophobic domain 1 of Pen-2 are essential for complex formation and stability of gamma-secretase. We also demonstrated that hydrophobic domain 1 and the loop domain of Pen-2 are located in a water-containing cavity and are in short proximity to the presenilin C-terminal fragment. We finally demonstrated the essential role of Pen-2 for the proteolytic activity of the complex. Our study supports the hypothesis that Pen-2 is more than a structural component of the gamma-secretase complex and may contribute to the catalytic mechanism of the enzyme.
引用
收藏
页码:12271 / 12282
页数:12
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